Short lived radioactive isotopes produced from radionuclide generators are commonly used in diagnostic nuclear medicine and in biomedical researches. The Tc-99m generator is a well-known example of a widely used generator used in single photon emission computed tomography (SPECT) for diagnostic imaging.
With the rapid expansion of the technique of tomographic reconstruction in Positron Emission Tomography (PET) imaging, the supply of positron emitting radionuclides has become crucial. The use of short lived radioisotopes 18F, 11C and 15O in PET imaging is well established. Unfortunately, these short-lived (half-life less than 2 hours) positron emitting radionuclides are all only available from expensive on-site cyclotrons operating in relatively few major hospitals. It is desirable to expand the use of positron emitting radionuclides produced from radionuclide generators in order to provide the superior benefits of PET based molecular imaging.
Of those positron emitting nuclides which may be produced by a generator, 68Ga isotope, with its desirable half-life of 68 minutes and generated from a long lived parent 68Ge of 287-day half-life, is known to have the highest potential for widespread and cost-effective application in daily clinical PET practice.
Bio-medically, ongoing research activities and current nuclear medicine applications of 68Ga are based on its favourable properties. Gallium is known as the second most effective chemotherapeutic agent after platinum due to its high and specific affinity toward tumour tissues. Well-known coordination chemistry of gallium is advantageous for radio-labelling of radiopharmaceuticals. The readiness of the 68Ga radioactive isotope to couple to small bio-molecules makes it potentially an alternative to 18F- and 11C-based PET radio-pharmacy. Several chelate compounds developed for radiolabelling of peptides and/or protein entities with metallic radionuclides are well suited to 68Ga labelling, 68Ga currently finds significant application in conventional nuclear medicine practice. To cite just two examples, 68Ga-EDTA is used for the detection of blood-brain barrier integrity and 68Ga-PLED and 68Ga-EDTA are used for renal function investigation.
68Ga based PET radiopharmaceuticals under phase III clinical trial include 68Ga-DOTA-NOC (68Ga-1,4,7,10-tetraazacyclo-dodecane-N,N′,N″,N″-tetraacetic acid-1-Nal3-octreotide), 68Ga-DOTA-TATE (68Ga-1,4,7,10-tetraazacyclo-dodecane-N,N′,N″,N″-tetraacetic acid-tyrosine-3-octreotate), 68Ga-DOTA-Lanreotide (68Ga-DOTA-2-NaI-Tyr3-ThrNH28-octreotide) and 68Ga-DOTA-TOC (68Ga-1,4,7,10-tetraazacyclo-dodecane-N,N′,N″,N″-tetraacetic acid-tyrosine-3-octreotide) for PET imaging of several subtypes of somatostatin receptors for the imaging neuroendocrin tumor; 68Ga-DOTA-Bombesin (68Ga-1,4,7,10-tetraazacyclo-dodecane-N,N′,N″,N″-tetraacetic acid DOTA-Bombesin) for PET imaging of gastro-intestinal, stromal, colon and prostate cancer; 68Ga-AMBA (68Ga-DO3A-CH2CO-Gly-4-aminobenzoy-Q-W-A-V-G-H-L-M-NH2) and 68Ga-DOTA-D-Glu] gastrin (68Ga-1,4,7,10-tetraazacyclo-dodecane-N,N′,N″,N″-tetraacetic acid-D-Glu] gastrin) for studies on NMB and GRP—R bombesin receptors and on medullary thyroid cancer, respectively.
With regard to its nuclear physics, 68Ga is considered as the second most important β+ emitter (after 18F), and may be efficiently used in PET imaging. It has the following favourable characteristics:    i. High positron abundance and good imaging resolution: 89.14% atoms decay β+ particles (with 511 KeV annihilation gamma ray of 178.2% intensity). 829.5 KeV positron radiation provides a PET imaging resolution of about 2.3 mm (bone) and 11.5 mm (lung) for living tissues (compared to 0.65 mm and 2.7 mm in the case of 18F). These values are well within the system resolution of modern PET cameras (about 4-5 mm) and are usable with high resolution PET system (resolution of about 3 mm).    ii. No associated gamma impact on PET images: insignificant amounts of associated gamma emissions (0.03407%) falling within the commonly used PET energy window of 350-700 KeV has almost no impact on PET images.    iii. Good conformation to conventional radiation safety: the Γ20 KeV exposure rate constant of 0.179 μSv·m2/MBq·h (compared to 0.188 μSv·m2/MBq·h for 18F) makes the use of 18FDG standard radiation safety automatic infusion system feasible.In regard to economics and convenience of use 68Ga offers the following advantages.            Cost-effectiveness and on-demand availability: the long-lived parent nuclide 68Ge offers cost-effective PET imaging for a generator shelf-life of about 2 years.        A 68Ge/68Ga generator also renders the 68Ga based PET radio-pharmacy independent of an onsite cyclotron. This means that this generator is ideally suited to on-demand availability of β+ emitter for biomedical experiments and clinical targeting imaging both in remote PET centres without cyclotron and also in cyclotron-operating PET centres.        
It is predicted that 68Ga will become the 99mTc for PET/CT. Kit-formulated precursors along with the use of 68Ga generators, similar to the 99mTc in vivo kits, will enable these generators to become the mainstays of molecular imaging nuclear medicine.
To be successfully applied for, formulating 68Ga based targeting radiopharmaceuticals used in clinical PET imaging, and also for radiation safety reason, 68Ga solution produced from a 68Ge/68Ga generator should be of very high radionuclidic purity, i.e. the 68Ge parent nuclide contamination in the 68Ga solution should be very low (preferably <10−3%), due to long half-life of the 68Ge radionuclide. Additionally, chemical impurities, particularly metallic ion contaminants, in the 68Ga solution, should be kept as low, as possible to eliminate any concurrent coordination chemistry reactions which may reduce 68Ga labelling yield.
The availability of 68Ga solutions of high radioactive concentration (i.e. radioactivity per unit volume, Ci/mL) is also an important factor affecting the suitability of 68Ga for labelling micro quantities of biomedical substances currently used in the targeting radiopharmaceutical development.
In the past 68Ge/68Ga generator systems were developed based on two different techniques. In the first technique, solvent extraction methods using acetylacetone-carbon tetrachloride/dilute HCl solution and 8-hydroxyquinoline/chloroform were used by different research groups (G. I. Gleason, Int. J. App. Radiat. Isotopes, 8, 90 (1960); Iofa et al., Radiokhemiya, 12, 796 (1970); Gary J. Erhardt et al., J. Nucl. Med., 19 (1978)). In a second technique, column based 68Ge/68Ga generators were developed using different sorbents as generator column packing materials and alkaline, acidic or complexing agent containing aqueous solutions as eluents to separate 68Ga by an elution process from the parent nuclide 68Ge which was immobilized on the column. Among the column techniques that have been used, the following ones are worth mentioning.
Organic ion exchanger resin (Bio-Rad AG1-X8) column based 68Ga generator with elution with dilute HF solution and synthetic chelate resin (made by condensation of pyrogallol and formaldehyde) column based 68Ga generators were studied (R. D. Neirinckx et al., J. Nucl. Med., 21, 81-83 (1980); R. D. Neirinckx et al., Int. J. Appl. Radiat. Isot. 33, 259-266 (1982); R. D. Neirinckx et al., U.S. Pat. No. 4,264,468, Apr. 28, 1981; R. D. Neirinckx et al., U.S. Pat. No. 4,288,424, Sep. 8, 1981). Unfortunately, the radiation sensitivity of the organic matrices was unfavourable for the desired lifetime (at least about two years) of a 68Ga generator.
Alumina column combined with elution with dilute (0.005M) EDTA solution (M. W. Greene et al., Int. J. Appl. Radiat. Isot. 12, 62-63 (1961); P. Kopecky et al., Int. J. Appl. Radiat. Isot. 24, 73-80 (1973)) or high temperature treated alumina column combined with elution with dilute (0.1-0.2 M) HCl solution (S. Kh. Egamediev et al., J. Radioanal. Nucl. Chem., 246, 593-596 (2000); P. Kopecky et al., Int. J. Appl. Radiat. Isot. 25, 263-268 (1974)) was investigated for 68Ge/68Ga generator development. Use of an alumina column based 68Ga generator with alkaline solution elution was also patented (R. E. Lewis et al., U.S. Pat. No. 4,330,507, May 18, 1982). The high content of Al3+ ion in the 68Ga eluate, the use of a complexing agent (EDTA) containing solution for the elution and 68Ga eluate of low radioactive concentration were disadvantages for labelling PET radiopharmaceuticals.
Tin dioxide column based 68Ga generator with elution with 0.6 M-1.0 M HCl solutions was developed and is currently used (K. Aardaneh et al, J. Radioanal. Nucl. Chem., 268, 25-32 (2006); C. Loc'h et al, J. Nucl. Med., 21, 171-173 (1980); S. L. Waters et al., Int. J. Appl. Radiat. Isot. 34, 1023 (1983); K. D. McElvany et al, Int. J. Appl. Radiat. Isot. 35, 521-524 (1984)). The high content of metallic ion impurities in the 68Ga eluate, the use of stronger acidic solution for the elution and the 68Ga eluate of low radioactive concentration are undesirable factors in this system for the process of coordination chemistry labelling of PET radiopharmaceuticals.
Hydrous zirconium-oxide column based 68Ga generators with 0.1M-0.5 M HCl or HNO3 solution elution were studied (P. J. Pao et al., J. Radioanal. Chem., 64, 267-272 (1981); R. D. Neirinckx et al, J. Nucl. Med., 20, 1075-1079 (1979)). Undesirably large volumes of eluent were necessary to elute 68Ga from the zirconium dioxide column and low 68Ga elution yield was reported.
Titanium dioxide, silicon dioxide, glass microsphere sorbents and cerium dioxide column based 68Ga generators with 0.1 M HCl solution elution have been reported (M. D. Kozlova et al., J. Lab. Comp. Radiopharm., 35, 282 (1994); R. D. Neirinckx et al., J. Nucl. Med., 20, 1075-1079 (1979); B. Bao et al., J. Radioanal. Nucl. Chem. Letters, 213, 233-238 (1996); G. J. Ehrhardt et al, U.S. Pat. No. 5,154,897, Oct. 13, 1992). Besides the low radioactive concentration of 68Ga eluate obtained, the metallic ion impurities from dissolution of column packing materials remains a problem to be solved for these systems.
Polyantimonic acid column based 68Ga generators using elution with sodium oxalate solution were unsuitable for coordination chemistry labelling of targeting radiopharmaceuticals due to the capability of 68Ga to form stable complexes with oxalate (H. Arino et al, Int. J. Appl. Radiat. Isot. 29, 117-120 (1978)).
Currently commercial 68Ge/68Ga generators are available based on a modified titanium dioxide column using 0.1 M HCl solution elution (Ecker & Ziegler Eurotope GmbH Berlin, Germany; Cyclotron Co. Ltd., Obninsk, Russia) and on a tin dioxide column using 0.6 M HCl solution elution (I.D.B Holland B.V.). The 5 mL 68Ga eluate and unavoidable high metallic ion contamination make the direct utilization of these for use in labelling radiopharmaceuticals impossible. Moreover the critical level of 68Ge breakthrough and acidity of the 68Ga eluate produced from these generator systems also present disadvantages which require further development of alternative sorbents for generator performance improvement.
In general, and particularly in radionuclide generator technology, useful sorbents require high chemical separation specificity, high radiation resistance and high chemical stability. The inorganic sorbents currently in use commonly have a hydrated amorphous structure, which is disadvantageous for chemical and physical stability. The low physical stability causes the sorbent particles to break easily and consequently the flow of fluid in the sorbent bed of chromatographic column is blocked or impeded. The low chemical stability causes leaching of metal ions from the sorbent material into the separated solute product, leading to contamination of the product with sorbent metal ions.